IRESSA- gefitinib tablet, coated AstraZeneca Pharmaceuticals LP----------

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use IRESSA safely andeffectively. See full prescribing information for IRESSA.IRESSA (gefitinib) tablets for oral useInitial U.S. Approval: 2015

INDICATIONS AND USAGEIRESSA is a tyrosine kinase inhibitor indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. (1)Limitation of Use: Safety and efficacy of IRESSA have not been established in patients whose tumors haveEGFR mutations other than exon 19 deletions or exon 21 (L858R) substitution mutations. (1)

DOSAGE AND ADMINISTRATIONRecommended dose is 250 mg orally, once daily with or without food. (2.2)

DOSAGE FORMS AND STRENGTHSTablets: 250 mg. (3)

CONTRAINDICATIONSNone. (4)

WARNINGS AND PRECAUTIONS

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ADVERSE REACTIONSThe most commonly reported adverse drug reactions (ADRs), reported in more than 20% of the patientsand greater than placebo were skin reactions and diarrhea. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDAat 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

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USE IN SPECIFIC POPULATIONSLactation: Discontinue breast-feeding. (8.2) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 5/2021

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Interstitial lung disease (ILD): ILD occurred in patients taking IRESSA. Withhold IRESSA for worsening ofrespiratory symptoms. Discontinue IRESSA if ILD is confirmed. (2.4, 5.1)Hepatotoxicity: Obtain periodic liver function testing. Withhold IRESSA for Grade 2 or higher for ALTand/or AST elevations. Discontinue for severe hepatic impairment. (2.4, 5.2)Gastrointestinal perforation: Discontinue IRESSA for gastrointestinal perforation. (2.4, 5.3)Diarrhea: Withhold IRESSA for Grade 3 or higher diarrhea. (2.4, 5.4)Ocular Disorders including Keratitis: Withhold IRESSA for signs and symptoms of severe or worseningocular disorders including keratitis. Discontinue for persistent ulcerative keratitis. (2.4, 5.5)Bullous and Exfoliative Skin Disorders: Withhold IRESSA for Grade 3 or higher skin reactions orexfoliative conditions. (2.4, 5.6)Embryo-fetal Toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effectivecontraception. (5.7, 8.1, 8.3)

CYP3A4 Inducer: Increase IRESSA to 500 mg daily in patients receiving a strong CYP3A4 inducer. (2.4,7.1)CYP3A4 Inhibitor: Monitor adverse reactions if concomitant use with IRESSA. (7.1)Drugs Affecting Gastric pH: Avoid concomitant use of IRESSA with proton pump inhibitors, if possible.(7.1)Hemorrhage in patients taking warfarin: Monitor changes in prothrombin time or INR. (7.2)

FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection2.2 Recommended Dose2.3 Administration to Patients Who Have Difficulty Swallowing Solids2.4 Dose Modification

3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS

5.1 Interstitial Lung Disease (ILD)5.2 Hepatotoxicity5.3 Gastrointestinal Perforation5.4 Severe or Persistent Diarrhea5.5 Ocular Disorders including Keratitis5.6 Bullous and Exfoliative Skin Disorders5.7 Embryo-fetal Toxicity

6 ADVERSE REACTIONS6.1 Clinical Trials Experience6.2 Postmarketing Experience

7 DRUG INTERACTIONS7.1 Drugs Affecting Gefitinib Exposure7.2 Hemorrhage in Patients taking Warfarin

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.2 Lactation8.3 Females and Males of Reproductive Potential8.4 Pediatric Use8.5 Geriatric Use8.6 Renal Impairment8.7 Hepatic Impairment

10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION*

FULL PRESCRIBING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS AND USAGEIRESSA is indicated for the first-line treatment of patients with metastatic non-small celllung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test [see Clinical Studies (14)].Limitation of Use: Safety and efficacy of IRESSA have not been established in patientswith metastatic NSCLC whose tumors have EGFR mutations other than exon 19deletions or exon 21 (L858R) substitution mutations [see Clinical Studies (14)].

2 DOSAGE AND ADMINISTRATION

2.1 Patient SelectionSelect patients for the first-line treatment of metastatic NSCLC with IRESSA based on thepresence of EGFR exon 19 deletions or exon 21 L858R mutations in their tumor orplasma specimens [see Indications and Usage (1), Clinical Studies (14)]. If thesemutations are not detected in a plasma specimen, test tumor tissue if feasible.Information on FDA-approved tests for the detection of EGFR mutations in NSCLC isavailable at: http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended DoseThe recommended dose of IRESSA is 250 mg orally once daily with or without food untildisease progression or unacceptable toxicity.Do not take a missed dose within 12 hours of the next dose.

2.3 Administration to Patients Who Have Difficulty Swallowing SolidsImmerse IRESSA tablets in 4 to 8 ounces of water by dropping the tablet in water, andstir for approximately 15 minutes. Immediately drink the liquid or administer through anaso-gastric tube. Rinse the container with 4 to 8 ounces of water and immediately drinkor administer through the naso-gastric tube.

2.4 Dose ModificationDose Modifications for Adverse Drug Reactions

Withhold IRESSA (for up to 14 days) for any of the following:

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Resume treatment with IRESSA when the adverse reaction fully resolves or improves to

Acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever) [seeWarnings and Precautions (5.1)]NCI CTCAE Grade 2 or higher in ALT and/or AST elevations [see Warnings andPrecautions (5.2)]NCI CTCAE Grade 3 or higher diarrhea [see Warnings and Precautions (5.4)]Signs and symptoms of severe or worsening ocular disorders including keratitis[see Warnings and Precautions (5.5)]NCI CTCAE Grade 3 or higher skin reactions [see Warnings and Precautions (5.6)]

NCI CTCAE Grade 1.Permanently discontinue IRESSA for:

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Dose Modifications for Drug Interactions

Strong CYP3A4 Inducers

Increase IRESSA to 500 mg daily in the absence of severe adverse drug reaction, andresume IRESSA at 250 mg seven days after discontinuation of the strong CYP3A4inducer [see Drug Interactions (7), Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS250 mg tablets: round, biconvex, brown film-coated, debossed with "IRESSA 250" onone side and plain on the other side.

4 CONTRAINDICATIONSNone.

5 WARNINGS AND PRECAUTIONS

5.1 Interstitial Lung Disease (ILD)ILD or ILD-like adverse drug reactions (e.g., lung infiltration, pneumonitis, acuterespiratory distress syndrome, or pulmonary fibrosis) occurred in 1.3% of the 2462patients who received IRESSA across clinical trials; of these, 0.7% were Grade 3 orhigher and 3 cases were fatal.Withhold IRESSA and promptly investigate for ILD in any patient who presents withworsening of respiratory symptoms such as dyspnea, cough and fever. Permanentlydiscontinue IRESSA if ILD is confirmed [see Dosage and Administration (2.4), AdverseReactions (6.1)].

5.2 HepatotoxicityIn patients who received IRESSA across clinical trials, 11.4% of patients had increasedalanine aminotransferase (ALT), 7.9% of patients had increased aspartateaminotransferase (AST), and 2.7% of patients had increased bilirubin. Grade 3 or higherliver test abnormalities occurred in 5.1% (ALT), 3.0% (AST), and 0.7% (bilirubin) ofpatients. The incidence of fatal hepatotoxicity was 0.04%.Obtain periodic liver function testing. Withhold IRESSA in patients with worsening liverfunction and discontinue in patients with severe hepatic impairment [see Dosage andAdministration (2.4), Adverse Reactions (6.1), Use in Specific Populations (8.7)].

Confirmed interstitial lung disease (ILD) [see Warnings and Precautions (5.1)]Severe hepatic impairment [see Warnings and Precautions (5.2)]Gastrointestinal perforation [see Warnings and Precautions (5.3)]Persistent ulcerative keratitis [see Warnings and Precautions (5.5)]

5.3 Gastrointestinal PerforationGastrointestinal perforation occurred in three (0.1%) of the 2462 IRESSA-treatedpatients across clinical trials [see Adverse Reactions (6.1)]. Permanently discontinueIRESSA in patients who develop gastrointestinal perforation [see Dosage andAdministration (2.4)].

5.4 Severe or Persistent DiarrheaGrade 3 or 4 diarrhea occurred in 3% of 2462 IRESSA-treated patients across clinicaltrials. Withhold IRESSA for severe or persistent (up to 14 days) diarrhea [see Dosageand Administration (2.4), Adverse Reactions (6.1)].

5.5 Ocular Disorders including KeratitisOcular disorders [keratitis (0.1%), corneal erosion and aberrant eyelash growth (0.2%),conjunctivitis, blephritis and dry eye (6.7%)] occurred in the 2462 IRESSA-treatedpatients across clinical trials. The incidence of Grade 3 ocular disorders was 0.1% [seeAdverse Reactions (6.1)]. Interrupt or discontinue IRESSA for severe, or worseningocular disorders [see Dosage and Administration (2.4)].

5.6 Bullous and Exfoliative Skin DisordersBullous conditions including toxic epidermal necrolysis, Stevens Johnson syndrome anderythema multiforme have been reported from treatment with IRESSA. Erythemamultiforme and dermatitis bullous have been reported in two patients (0.08%) acrossNSCLC trials (Study 2, Study 3 and Study 4). IRESSA treatment should be interrupted ordiscontinued if the patient develops severe bullous, blistering or exfoliating conditions.

5.7 Embryo-fetal ToxicityBased on its mechanism of action and data from animal reproduction studies IRESSAcan cause fetal harm when administered to a pregnant woman. In animal reproductivestudies, oral administration of gefitinib from organogenesis through weaning resulted infetotoxicity and neonatal death at doses below the recommended human dose. Advisepregnant women of the potential risk to a fetus. Advise females of reproductive potentialto use effective contraception during treatment with IRESSA and for at least two weeksfollowing completion of therapy [see Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONSThe following adverse drug reactions are discussed in more detail in other sections ofthe labeling:

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6.1 Clinical Trials Experience

Interstitial Lung Disease [see Warnings and Precautions (5.1)]Hepatotoxicity [see Warnings and Precautions (5.2)]Gastrointestinal Perforation [see Warnings and Precautions (5.3)]Severe or Persistent Diarrhea [see Warnings and Precautions (5.4)]Ocular Disorders including Keratitis [see Warnings and Precautions (5.5)]Bullous and Exfoliative Skin Disorders [see Warning and Precautions (5.6)]

Because clinical trials are conducted under widely varying conditions, adverse reactionrates observed in the clinical trials of a drug cannot be directly compared to rates in theclinical trials of another drug and may not reflect the rates observed in practice.The safety of IRESSA is based on the data from 2462 patients with NSCLC who receivedIRESSA 250 mg daily monotherapy in three randomized clinical studies (Study 2, Study 3and Study 4). Patients with a history of interstitial lung disease, drug-induced interstitialdisease, radiation pneumonitis that required steroid treatment or any evidence ofclinically active interstitial lung disease were excluded from these studies.Controlled Studies:Study 2 was a randomized, multicenter, open-label trial in which 1217 patients wererandomized to receive first-line treatment for metastatic NSCLC; 607 patients receivedIRESSA 250 mg daily and 589 patients received carboplatin/paclitaxel. The medianduration of treatment with IRESSA was 5.9 months. The study population characteristicswere: median age 57 years, age less than 65 years (73%), female (79%), Asian (100%),NSCLC adenocarcinoma histology (100%), never smoker (94%), light ex-smoker (6%),ECOG PS 0 or 1 (90%).Study 3 was a randomized, multicenter, double-blind, placebo-controlled trial in which1692 patients were randomized to receive second- or third-line treatment for metastaticNSCLC; of which 1126 patients received IRESSA 250 mg daily and 562 patients receivedplacebo. The median duration of treatment with IRESSA was 2.9 months. The studypopulation characteristics were: median age 62 years, age less than 65 years (60%),female (33%), Caucasian (75%), Asian (21%), NSCLC adenocarcinoma histology (48%),never smoker (22%), ECOG PS 0 or 1 (65%), PS 2 (29%), PS 3 (5%) and two or moreprior therapies (51%).Study 4 was a randomized, multicenter, open-label trial in which 1466 patients wererandomized to receive second-line treatment for metastatic NSCLC; 729 patientsreceived IRESSA 250 mg daily and 715 patients received docetaxel. The median durationof treatment with IRESSA was 2.4 months. The study population characteristics were:median age 61 years, age less than 65 years (61%), female (36%), Caucasian (79%),Asian (21%), NSCLC adenocarcinoma histology (54%), never smoker (20%), ECOG PS 0or 1 (88%) and two or more prior therapies (16%).The pooled safety database from the three randomized trials was used to evaluate forserious and uncommon adverse drug reactions. Common adverse reactions wereevaluated in Study 3. The most frequent adverse reactions in Study 3 (incidence of>20% and greater than placebo) reported in IRESSA-treated patients were skinreactions (47%) and diarrhea (29%). The most frequent fatal adverse reactions inIRESSA-treated patients were respiratory failure (0.9%), pneumonia (0.8%), andpulmonary embolism (0.5%).Approximately 5% of IRESSA-treated patients and 2.3% of placebo-treated patientsdiscontinued treatment due to an adverse event. The most frequent adverse reactionsthat led to discontinuation in patients treated with IRESSA were nausea (0.5%), vomiting(0.5%) and diarrhea (0.4%).

Table 1 - Selected Adverse Drug Reactions Occurring with an Incidence Rate≥5% and an Increase of >2% of IRESSA-treated Patients in Study 3

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Adverse Reaction Percentage (%) of patientsIRESSA (N=1126) Placebo (N=562)

All Grades Grade 3 and 4 All Grades Grade 3 and4

Skin and subcutaneous tissue disordersSkin reactions 47% 2% 17% 0.4%Nail disorders 5% 0.1% 0.7% 0%Gastrointestinal disordersDiarrhea 29% 3% 10% 1%Vomiting 14% 1.2% 10% 0.4%Stomatitis 7% 0.3% 4% 0.2%Metabolism and nutrition disordersDecreased appetite 17% 2.3% 14% 2.0%Eye disordersConjunctivitis/blepharitis/dryeye 6% 0% 3.2% 0%

Table 2 - Treatment Emergent Laboratory Abnormalities Occurring MoreFrequently in IRESSA-Treated Patients in Study 3

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Adverse Reaction IRESSA PlaceboAll Grades

%Grade 3 and

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All Grades%

Grade 3 and4%

Alanine aminotransferaseincreased

38% 2.4% 23% 1.4%

Aspartate aminotransferaseincreased

40% 2.0% 25% 1.3%

Proteinuria 35% 4.7% 31% 3.3%

The following adverse reactions have been reported with IRESSA across NSCLC trials(Study 2, Study 3 and Study 4) and are not listed elsewhere in Section 6: nausea (18%),asthenia (17%), pyrexia (9%), alopecia (4.7%), hemorrhage (including epistaxis andhematuria) (4.3%), dry mouth (2%), dehydration (1.8%), elevations in blood creatinine(1.5%), allergic reactions including angioedema and urticaria (1.1%), palmar-plantar

Includes Acne, Acne pustular, Dermatitis, Dermatitis acneiform, Dermatitis exfoliative, Drugeruption, Dry skin, Erythema, Exfoliative rash, Folliculitis, Pruritus, Pruritus generalized, Rash, Rasherythematous, Rash generalized, Rash macular, Rash maculo-papular, Rash papular, Rash pruritic,Rash pustular, Rash vesicular, Skin exfoliation, Skin toxicity, XerodermaIncludes Ingrowing nail, Nail bed infection, Nail disorder, Nail infection, Onychoclasis, Onycholysis,ParonychiaIncludes Diarrhea, Feces soft, Frequent bowel movementsIncludes Aphthous stomatitis, Cheilitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oralmucosal blistering, Stomatitis, Tongue disorder, Tongue ulcerationIncludes Blepharitis, Conjunctival hyperemia, Conjunctivitis, Dry eye, Eye irritation, Eye pruritus, Eyeswelling, Eyelid irritation, Eyelid edema, Eyelids pruritus

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Patients were allowed to enter the clinical study with lab values of ALT or AST CTCAE grade 1 or 214% gefitinib patients and 10% placebo patients were CTC grade 1 or 2 ALT at baseline0.2% of placebo patients were CTC grade 3 at baseline15% gefitinib patients and 12% placebo patients were CTC grade 1 or 2 AST at baseline0.4% of placebo patients were CTC grade 3 at baseline

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erythrodysesthesia syndrome (0.2%) and pancreatitis (0.1%).

6.2 Postmarketing ExperienceThe following adverse reactions have been identified during post-approval use ofIRESSA. Because these reactions are reported voluntarily from a population of uncertainsize, it is not always possible to reliably estimate their frequency or establish a causalrelationship to drug exposure.Renal and urinary disorders: cystitis, hemorrhagic cystitisSkin and subcutaneous tissue disorders: cutaneous vasculitis

7 DRUG INTERACTIONS

7.1 Drugs Affecting Gefitinib ExposureCYP3A4 Inducer

Drugs that are strong inducers of CYP3A4 increase the metabolism of gefitinib anddecrease gefitinib plasma concentrations. Increase IRESSA to 500 mg daily in patientsreceiving a strong CYP3A4 inducer (e.g., rifampicin, phenytoin, or tricyclicantidepressant) and resume IRESSA at 250 mg 7 days after discontinuation of thestrong inducer [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].CYP3A4 Inhibitor

Drugs that are strong inhibitors of CYP3A4 (e.g., ketoconazole and itraconazole)decrease gefitinib metabolism and increase gefitinib plasma concentrations. Monitoradverse reactions when administering strong CYP3A4 inhibitors with IRESSA.Drugs Affecting Gastric pH

Drugs that elevate gastric pH (e.g., proton pump inhibitors, histamine H -receptorantagonists, and antacids) may reduce plasma concentrations of gefitinib. Avoidconcomitant use of IRESSA with proton pump inhibitors, if possible. If treatment with aproton-pump inhibitor is required, take IRESSA 12 hours after the last dose or 12 hoursbefore the next dose of the proton-pump inhibitor. Take IRESSA 6 hours after or 6hours before an H -receptor antagonist or an antacid [see Clinical Pharmacology (12.3)].

7.2 Hemorrhage in Patients taking WarfarinInternational Normalized Ratio (INR) elevations and/or hemorrhage have been reportedin some patients taking warfarin while on IRESSA therapy. Patients taking warfarinshould be monitored regularly for changes in prothrombin time or INR.

8 USE IN SPECIFIC POPULATIONS

8.1 PregnancyRisk SummaryBased on its mechanism of action and animal data, IRESSA can cause fetal harm whenadministered to a pregnant woman. In animal reproductive studies, oral administration

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of gefitinib from organogenesis through weaning resulted in fetotoxicity and neonataldeath at doses below the recommended human dose (see Animal Data). Advisepregnant women of the potential hazard to a fetus or potential risk for loss of thepregnancy.The background risk of major birth defects and miscarriage for the indicated populationis unknown; however, the background risk in the U.S. general population of major birthdefects is 2-4% and miscarriage is 15-20% of clinically recognized pregnancies.DataAnimal Data

A single dose study in rats showed that gefitinib crosses the placenta after an oral doseof 5 mg/kg (30 mg/m , about 0.2 times the recommended human dose on a mg/mbasis). When pregnant rats were treated with 5 mg/kg from the beginning oforganogenesis to the end of weaning there was a reduction in the number of offspringborn alive. This effect was more severe at 20 mg/kg (approximate the human clinicaldose on a mg/m basis) and was accompanied by high neonatal mortality soon afterparturition. In rabbits, a dose of 20 mg/kg/day (240 mg/m , about twice therecommended dose in humans on a mg/m basis) caused reduced fetal weight.

8.2 LactationRisk SummaryIt is not known whether IRESSA is excreted in human milk. Animal studies indicate thegefitinib and its metabolites are present in rat milk at a concentration higher than thosein maternal plasma. Because of the potential for serious adverse reactions in nursinginfants from IRESSA, advise women to discontinue breast-feeding during treatment withIRESSA.DataAnimal Data

Levels of gefitinib and its metabolites were 11-to-19-fold higher in milk than in blood,after oral exposure of lactating rats to a dose of 5 mg/kg.

8.3 Females and Males of Reproductive PotentialContraceptionBased on its mechanism of action and animal data, IRESSA can cause fetal harm whenadministered to a pregnant woman [see Use in Specific Populations (8.1)]. Advisefemales of reproductive potential to use effective contraception during treatment withIRESSA and for at least two weeks following completion of therapy.InfertilityIRESSA may result in reduced fertility in females of reproductive potential [see NonclinicalToxicology (13.1)].

8.4 Pediatric UseThe safety and effectiveness of IRESSA in pediatric patients have not been established.

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8.5 Geriatric UseOf the 823 patients enrolled in two randomized, active-controlled clinical trials 374patients (45%) were 65 years and older, and 93 patients (11%) were 75 years and older.No overall differences in safety were observed between patients 65 years and older andthose younger than 65 years. There is insufficient information to assess for differencesin efficacy between older and younger patients.

8.6 Renal ImpairmentLess than four percent (<4%) of gefitinib and its metabolites are excreted via the kidney.No clinical studies were conducted with IRESSA in patients with severe renal impairment.

8.7 Hepatic ImpairmentThe systemic exposure of gefitinib was compared in patients with mild, moderate, orsevere hepatic impairment due to cirrhosis (according to Child-Pugh classification) andhealthy subjects with normal hepatic function (N=10/group). The mean systemicexposure (AUC ) was increased by 40% in patients with mild impairment, 263% inpatients with moderate impairment, and 166% in patients with severe hepaticimpairment. Monitor adverse reactions when IRESSA is administered to patients withmoderate and severe hepatic impairment.In a study comparing 13 patients with liver metastases and moderate hepaticimpairment (addition of CTC grade of baseline AST/SGOT, ALP, and bilirubin equals 3 to5) to 14 patients with liver metastases and normal hepatic function, the systemicexposure of gefitinib was similar [see Warnings and Precautions (5.2)].

10 OVERDOSAGETwenty three patients were treated weekly with doses from 1500 mg to 3500 mg, andIRESSA exposure did not increase with increasing dose. Adverse events were mostlymild to moderate in severity, and were consistent with the known safety profile ofIRESSA. In the event of suspected overdose, interrupt IRESSA, institute supportive care,and observe until clinical stabilization. There are no specific measures/treatments thatshould be taken following IRESSA overdosing.

11 DESCRIPTIONGefitinib is a kinase inhibitor.The chemical name of gefitinib is 4-Quinazolinamine N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl) propoxy] and the following structural formula:

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Gefitinib has the molecular formula C H ClFN O , a relative molecular mass of 446.9daltons and is a white-colored powder. Gefitinib is a free base. The molecule has pK s of5.4 and 7.2. Gefitinib can be defined as sparingly soluble at pH 1, but is practicallyinsoluble above pH 7, with the solubility decreasing sharply between pH 4 and pH 6. Innon-aqueous solvents, gefitinib is freely soluble in glacial acetic acid and dimethylsulfoxide, soluble in pyridine, sparingly soluble in tetrahydrofuran, and slightly soluble inmethanol, ethanol (99.5%), ethyl acetate, propan-2-ol and acetonitrile.IRESSA (gefitinib) tablets are available as brown film-coated tablets, containing 250 mgof gefitinib, for oral administration. The inactive ingredients of the tablet core of IRESSAtablets are lactose monohydrate, microcrystalline cellulose, croscarmellose sodium,povidone, sodium lauryl sulfate and magnesium stearate. The tablet coating is composedof hypromellose, polyethylene glycol 300, titanium dioxide, red ferric oxide and yellowferric oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of ActionThe epidermal growth factor receptor (EGFR) is expressed on the cell surface of bothnormal and cancer cells and plays a role in the processes of cell growth andproliferation. Some EGFR activating mutations (exon 19 deletion or exon 21 pointmutation L858R) within NSCLC cells have been identified as contributing to thepromotion of tumor cell growth, blocking of apoptosis, increasing the production ofangiogenic factors and facilitating the processes of metastasis.Gefitinib reversibly inhibits the kinase activity of wild-type and certain activatingmutations of EGFR, preventing autophosphorylation of tyrosine residues associated withthe receptor, thereby inhibiting further downstream signaling and blocking EGFR-dependent proliferation.Gefitinib binding affinity for EGFR exon 19 deletion or exon 21 point mutation L858Rmutations is higher than its affinity for the wild-type EGFR. Gefitinib also inhibits IGF andPDGF-mediated signaling at clinically relevant concentrations; inhibition of other tyrosinekinase receptors has not been fully characterized.

12.3 PharmacokineticsAbsorption and Distribution

The mean oral bioavailability of gefitinib is 60%, with peak plasma levels occurring 3-7

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hours after dosing. Food does not alter gefitinib bioavailability to a clinically meaningfulextent. IRESSA can be administered with or without food. Gefitinib is extensivelydistributed throughout the body with a mean steady state volume of distribution of 1400L following intravenous administration. In vitro binding of gefitinib to human plasmaproteins (serum albumin and α1-acid glycoprotein) is 90%, independent of drugconcentrations. Gefitinib is a substrate for the membrane transport P-glycoprotein (P-gp), but it is unlikely to influence gefitinib absorption as P-gp is saturated at higherconcentrations.Metabolism and Elimination

Gefitinib undergoes extensive hepatic metabolism in humans, predominantly by CYP3A4.Three sites of biotransformation have been identified: metabolism of the N-propoxymorpholino-group, demethylation of the methoxy-substituent on thequinazoline, and oxidative defluorination of the halogenated phenyl group. Fivemetabolites have been fully identified in fecal extracts and the major active componentwas O-desmethyl gefitinib produced by CYP2D6 metabolism and accounted for 14% ofthe dose.Eight metabolites were identified in human plasma. Only O-desmethyl gefitinib hasexposure comparable to gefitinib. Although this metabolite has similar EGFR-TK activityto gefitinib in the isolated enzyme assay, it had only 1/14 of the potency of gefitinib inone of the cell-based assays.Gefitinib is cleared primarily by the liver, with total plasma clearance and elimination half-life of 48 hours after intravenous administration. The inter-subject variability (coefficientof variation) for AUC in healthy subjects was 67%. Daily oral administration of gefitinib tocancer patients resulted in a two-fold accumulation compared to single doseadministration. Steady state plasma concentrations are achieved within 10 days afterdaily dosing. Excretion of gefitinib and its metabolites is predominantly via the feces(86%), with renal elimination accounting for less than 4% of the administered dose.Specific Populations

Age, gender, body weight, ethnicity or renal function: Population pharmacokineticanalyses suggest that patient age, body weight, ethnicity (populations included) orcreatinine clearance (above 20 mL/min) has no clinically meaningful effect on predictedsteady state trough concentration of gefitinib. Population pharmacokinetic analyses ofStudy 1 showed that women had 27% higher exposure than men; however, thisdifference was not identified in the analyses of other gefitinib clinical studies. No doseadjustment based on patient gender is recommended.Hepatic Impairment: The systemic exposure of gefitinib was compared between patientswith mild, moderate, or severe hepatic impairment due to cirrhosis (according to Child-Pugh classification) and healthy subjects with normal hepatic function (N=10/group).The mean systemic exposure (AUC0-∞) was increased by 40% in patients with mildimpairment, 263% in patients with moderate impairment, and 166% in patients withsevere hepatic impairment. In a study comparing 13 patients with liver metastases andmoderate hepatic impairment to 14 patients with liver metastases and normal hepaticfunction, the systemic exposure of gefitinib was similar [see Warnings and Precautions(5.2), Use in Specific Populations (8.7)].CYP2D6 Poor metabolizer: CYP2D6 metabolizes gefitinib to O-desmethyl gefitinib in vitro.In healthy CYP2D6 poor metabolizers, O-desmethyl gefitinib concentration was not

measurable and the mean exposure to gefitinib was 2-fold higher as compared to theextensive metabolizers. This increase in exposure in CYP2D6 poor metabolizers may beclinically important because some adverse drug reactions are related to higher exposureof gefitinib. No dose adjustment is recommended in patients with a known CYP2D6 poormetabolizer genotype, but these patients should be closely monitored for adversereactions. The impact of CYP2D6 inhibiting drugs on gefitinib pharmacokinetics has notbeen evaluated. However, similar precautions should be used when administeringCYP2D6 inhibitors with IRESSA because of the possibility of increased exposure in thesepatients.An exploratory exposure response analysis showed an increase in the incidence ofinterstitial lung disease (ILD) with a greater than 2-fold increase in the gefitinib exposure[see Warnings and Precautions (5.1)].Drug-Drug Interactions

Strong CYP3A4 Inducer:

Concomitant administration of rifampicin (600 mg QD for 16 days), a strong inducer ofCYP3A4, with gefitinib (500 mg single dose on Day 10 of gefitinib administration)reduced mean AUC of gefitinib by 83% [see Dosage and Administration (2.4), DrugInteractions (7)].CYP3A4 Inhibitor:

Concomitant administration of itraconazole (200 mg QD for 12 days), an inhibitor ofCYP3A4, with gefitinib (250 mg single dose on Day 4 of itraconazole administration) tohealthy male subjects, increased mean gefitinib AUC by 80% [see Drug Interactions (7)].Drugs Affecting Gastric pH:

Co-administration of high doses of ranitidine with sodium bicarbonate (to maintain thegastric pH above pH 5.0) to healthy subjects decreased mean gefitinib AUC by 47% [seeDrug Interactions (7)].In human liver microsome studies, gefitinib had no inhibitory effect on CYP1A2, CYP2C9,and CYP3A4 activities at concentrations ranging from 2-5000 ng/mL. At the highestconcentration studied (5000 ng/mL), gefitinib inhibited CYP2C19 by 24% and CYP2D6 by43%.Exposure to metoprolol, a substrate of CYP2D6, was increased by 30% when it wasgiven on Day 15 of gefitinib dosing (500 mg daily for 28 days) in patients with solidtumors.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityGefitinib has been tested for genotoxicity in a series of in vitro (bacterial mutation,mouse lymphoma, and human lymphocyte) assays and an in vivo rat micronucleus test.Under the conditions of these assays, gefitinib did not cause genetic damage.In a two-year carcinogenicity study in mice, administration of gefitinib at a dose of 270mg/m /day (approximately twice the recommended daily dose of 250 mg on a mg/mbasis; dose reduced from 375 mg/m /day from week 22) caused hepatocellular

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adenomas in females. In a two-year carcinogenicity study in rats, administration ofgefitinib at 60 mg/m /day (approximately 0.4 times the recommended daily clinical doseon a mg/m basis) caused hepatocellular adenomas andhemangiomas/hemagiosarcomas of the mesenteric lymph nodes in female rats. Theclinical relevance of these findings is unknown.In a dedicated fertility study in rats at doses ≥120 mg/m (approximately equal to therecommended human dose of gefitinib on a mg/m basis), animals presented with anincreased incidence of irregular estrous, decreased corpora lutea, and decreases inuterine implants and live embryos per litter.

14 CLINICAL STUDIESNon-Small Cell Lung Cancer (NSCLC)Study 1

The efficacy and safety of IRESSA for the first-line treatment of patients with metastaticNSCLC containing EGFR exon 19 deletions or L858R substitution mutations wasdemonstrated in a multicenter, single-arm, open-label clinical study (Study 1). A total of106 treatment-naive patients with metastatic EGFR mutation positive NSCLC receivedIRESSA at a dose of 250 mg once daily until disease progression or intolerable toxicity.The major efficacy outcome measure was objective response rate (ORR) according toRECIST v1.1 as evaluated by both a Blinded Independent Central Review (BICR) andinvestigators. Duration of response (DOR) was an additional outcome measure. Eligiblepatients were required to have a deletion in EGFR exon 19 or L858R, L861Q, or G719Xsubstitution mutation and no T790M or S768I mutation or exon 20 insertion in tumorspecimens as prospectively determined by a clinical trial assay. Tumor samples from 87patients were tested retrospectively using the therascreen EGFR RGQ PCR Kit.The study population characteristics were: median age 65 years, age 75 years or older(25%), age less than 65 years (49%), white (100%), female (71%), never smokers(64%), WHO PS 0 (45%), WHO PS 1 (48%), WHO PS 2 (7%), and adenocarcinomahistology (97%). Sixty patients had exon 19 deletions (65%), 29 patients had L858Rsubstitution (31%), while two patients each had tumors harboring L861Q or G719Xsubstitution mutation.The median duration of treatment was 8.0 months. Efficacy results from Study 1 aresummarized below.

Table 3 – Efficacy Results in Study 1

*

Efficacy Parameter BICR Assessment(n=106)

InvestigatorAssessment

(n=106)Objective Response Rate(95% CI)

50%(41, 59)

70%(61, 78)

Complete Response Rate 0.9% 1.9%Partial Response Rate 49% 68%Median Duration of Response (months)(95% CI)

6.0(5.6, 11.1)

8.3(7.6, 11.3)

22

22

®

BICR, Blinded Independent Central Review17 patients without target lesion at baseline detected by BICR were deemed non responders

*†

‡

*†‡

The response rates were similar in patients whose tumors had EGFR exon 19 deletionsand exon 21 L858R substitution mutations. Two partial responses were observed inboth patients whose tumors had G719X substitution mutation with duration of responseof at least 2.8 months and 5.6 months, respectively. One of two patients whose tumorshad L861Q substitution mutation also achieved a partial response with duration ofresponse of at least 2.8 months.Study 2

The results of Study 1 were supported by an exploratory analysis of a subset of arandomized, multicenter, open-label trial (Study 2) conducted in patients with metastaticadenocarcinoma histology NSCLC receiving first-line treatment. Patients wererandomized (1:1) to receive IRESSA 250 mg orally once daily or up to 6 cycles ofcarboplatin/paclitaxel. The efficacy outcomes included progression-free survival (PFS)and objective response rate (ORR) as assessed by BICR.The subset population consisted of 186 of 1217 patients (15%) determined to be EGFRpositive by the same clinical trial assay as used in Study 1 and had radiographic scansavailable for a retrospective assessment by BICR. In this subset, there were 88 IRESSA-treated patients and 98 carboplatin/paclitaxel-treated patients.Demographic and baseline characteristics of this subset were a median age of 59 years,age 75 years or older (7%), age less than 65 (70%), Asian (100%), female (83%), neversmokers (96%), adenocarcinoma histology (100%), and PS 0-1 (94%).The median duration of treatment for IRESSA-treated patients was 9.8 months. Thehazard ratio for PFS favored the IRESSA-treated patients [HR of 0.54 (95% CI: 0.38,0.79)] with a median PFS of 10.9 months for the IRESSA-treated patients and 7.4months for the carboplatin/paclitaxel-treated patients as assessed by BICR. In addition,the objective response rate was 67% (95% CI: 56, 77) for IRESSA-treated patients and41% (95% CI: 31, 51) for carboplatin/paclitaxel-treated patients based on BICRassessment. The median duration of response was 9.6 months for IRESSA-treatedpatients and 5.5 months for carboplatin/paclitaxel-treated patients.

16 HOW SUPPLIED/STORAGE AND HANDLINGIRESSA (gefitinib) is available as 250 mg tablets.IRESSA 250 mg tablets are round, biconvex, brown film-coated, debossed with "IRESSA250" on one side and plain on the other side.IRESSA (gefitinib) tablets are supplied as:Bottles of 30 Tablets (NDC 0310-0482-30)Store at controlled room temperature 20°C-25°C (68°F-77°F) [see USP Controlled RoomTemperature].

17 PATIENT COUNSELING INFORMATION

17 patients without target lesion at baseline detected by BICR were deemed non respondersDetermined by RECIST v 1.1

®

®

Advise the patient to read the FDA-approved patient labelling (Patient Information).Interstitial Lung Disease: Advise patients to immediately contact their healthcare providerfor new onset or worsening of pulmonary symptoms such as dyspnea, cough and fever[see Warnings and Precautions (5.1)].Hepatotoxicity: Inform patients that they will need to undergo lab tests to monitor forliver function. Advise patients to contact their healthcare provider to report any newsymptoms indicating hepatic toxicity [see Warnings and Precautions (5.2)].Gastrointestinal Perforation: Advise patients that IRESSA can increase the risk ofgastrointestinal perforation and to seek immediate medical attention for severeabdominal pain [see Warnings and Precautions (5.3)].Severe or Persistent Diarrhea: Advise patients to contact their healthcare provider forsevere or persistent diarrhea [see Warnings and Precautions (5.4)].Ocular Disorders including Keratitis: Advise patients promptly to contact their healthcareprovider if they develop eye symptoms, lacrimation, light sensitivity, blurred vision, eyepain, red eye or changes in vision [see Warnings and Precautions (5.5)].Bullous and Exfoliative Skin Disorders: Advise patients that IRESSA can increase the riskof bullous and exfoliative skin disorders and to seek immediately medical attention forsevere skin reactions [see Warnings and Precautions (5.6)].Embryo-fetal Toxicity: Advise pregnant women of the potential risk to a fetus or potentialrisk for loss of the pregnancy [see Warnings and Precautions (5.7), Use in SpecificPopulations (8.1)]. Advise females of reproductive potential to use effectivecontraception during treatment with IRESSA and for at least two weeks followingcompletion of therapy [see Use in Specific Populations (8.3)].Lactation: Advise women to discontinue breast-feeding during treatment with IRESSA[see Use in Specific Populations (8.2)].IRESSA is a trademark of the AstraZeneca group of companies.©AstraZeneca 2021Distributed by:AstraZeneca Pharmaceuticals LPWilmington, DE 19850

Patient InformationIRESSA (eye-RES-sah)

(gefitinib) tablets

What is IRESSA?IRESSA is a prescription medicine used to treat people with non-small cell lung cancer(NSCLC) that has spread to other parts of the body and:

• that have certain types of abnormal epidermal growth factor receptor (EGFR)

•

Your healthcare provider will perform a test to make sure that IRESSA is right for you.It is not known if IRESSA is safe and effective in people with NSCLC that have othertypes of EGFR genes.It is not known if IRESSA is safe and effective in children. Before taking IRESSA, tell your healthcare provider about all of your medicalconditions, including if you:

••••

•

Tell your healthcare provider about all the medicines you take, including prescription andover-the-counter medicines, vitamins, or herbal supplements.If you take a proton pump inhibitor (PPI), H2 blocker, or an antacid medicine, talk toyour healthcare provider about the best time to take it during treatment with IRESSA.If you take a blood thinner called warfarin, your healthcare provider should do bloodtests regularly to check how fast your blood clots, during treatment with IRESSA. How should I take IRESSA?

••

•••

•

•

genes, andwho have not had previous treatment for cancer

have lung or breathing problemsever had liver problemshave vision or eye problemsare pregnant or plan to become pregnant. IRESSA can harm your unborn baby.

∘

∘

Females who are able to become pregnant should use an effective method ofbirth control during treatment with IRESSA and for at least 2 weeks after thelast dose of IRESSA. You should avoid becoming pregnant during treatmentwith IRESSA.Tell your healthcare provider right away if you become pregnant duringtreatment with IRESSA.

are breastfeeding or plan to breastfeed. It is not known if IRESSA passes into yourbreast milk. Do not breastfeed during treatment with IRESSA. Talk to yourhealthcare provider about the best way to feed your baby during this time.

Take IRESSA exactly as your healthcare provider tells you to take it.Your healthcare provider may change your dose, temporarily stop, or permanentlystop treatment with IRESSA if you have side effects.Take IRESSA 1 time each day.You can take IRESSA with or without food.If you miss a dose of IRESSA, take it as soon as you remember. If it is less than 12hours until your next dose, skip the missed dose. Take your next dose at yourregular time.If you take too much IRESSA, call your healthcare provider or go to the nearestemergency room right away.If you cannot swallow IRESSA tablets whole:

∘

∘

place your dose of IRESSA in a container with 4 to 8 ounces of water and stirfor about 15 minutesdrink the mixture right away

What are the possible side effects of IRESSA?IRESSA may cause serious side effects, including:

•

•

Your healthcare provider will do blood tests to check your liver function during yourtreatment with IRESSA.

•

•

•

•

IRESSA may cause fertility problems in females. Talk to your healthcare provider if youplan to become pregnant.Tell your healthcare provider if you have any side effect that bothers you or that doesnot go away.These are not all the possible side effects of IRESSA. For more information, ask yourhealthcare provider or pharmacist.Call your doctor for medical advice about side effects.You may report side effects to FDA at 1-800-FDA-1088. How should I store IRESSA?Store IRESSA at room temperature between 68˚F to 77˚F (20˚C to 25˚C)Keep IRESSA and all medicines out of the reach of children.General information about the safe and effective use of IRESSA.Medicines are sometimes prescribed for purposes other than those listed in PatientInformation leaflet. Do not use IRESSA for a condition for which it was not prescribed.

∘ place another 4 to 8 ounces of water in the same container, and drink it rightaway

lung or breathing problems. IRESSA may cause inflammation of the lung thatmay lead to death. Symptoms may be similar to those symptoms from lung cancer.Tell your healthcare provider right away if you have any new or worsening lungproblems, or any combination of the following symptoms: trouble breathing orshortness of breath, cough, or fever.liver problems. IRESSA may cause inflammation of the liver that may lead todeath. Tell your healthcare provider right away if you have any symptoms of a liverproblem which may include:

∘∘∘∘∘

yellowing of your skin or the white part of your eyes (jaundice)dark or brown (tea colored) urinelight-colored bowel movements (stools)decreased appetitepain on the right side of your stomach (abdomen)

a tear in the wall of your stomach or intestines (perforation). Getemergency medical help right away if you have severe stomach (abdomen) pain.diarrhea. Diarrhea is common with IRESSA and can sometimes be severe. Tellyour healthcare provider right away if you have severe diarrhea or diarrhea that willnot go away.eye problems. Tell your healthcare provider if you get watery eyes, sensitivity tolight, blurred vision, eye pain, eye redness, or vision changes.skin reactions. Skin redness, rash, itching, and acne are common with IRESSA.This may occur on any part of your body. Get medical help right away if youdevelop severe skin reactions such as peeling or blistering of your skin.

Do not give IRESSA to other people, even if they have the same symptoms you have. Itmay harm them. You can ask your healthcare provider or pharmacist for informationabout IRESSA that is written for health professionals. What are the ingredients in IRESSA?Active ingredient: gefitinibInactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellosesodium, povidone, sodium lauryl sulfate, magnesium stearateTablet coating contains: hypromellose, polyethylene glycol 300, titanium dioxide, yellowiron oxide and red iron oxide. IRESSA is a trademark of the AstraZeneca group of companies.©AstraZeneca 2021Distributed by:AstraZeneca Pharmaceuticals LPWilmington, DE 19850For more information, go to www.iressa.com or call 1-800-236-9933

This Patient Information has been approved by the U.S. Food and DrugAdministration. Issued: May 2021

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL – 250 mgNDC 0310-0482-30 30 tabletsIRESSA®(gefitinib) tablets250 mgManufactured for:AstraZeneca Pharmaceuticals LPWilmington, DE 19850By: AstraZeneca UK LimitedMacclesfield, Cheshire, EnglandProduct of BelgiumAstraZeneca

IRESSA gefitinib tablet, coated

Product InformationProduct Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0310-0482

Route of Administration ORAL

Active Ingredient/Active MoietyIngredient Name Basis of Strength Strength

GEFITINIB (UNII: S65743JHBS) (GEFITINIB - UNII:S65743JHBS) GEFITINIB 250 mg

Inactive IngredientsIngredient Name Strength

LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) POVIDONE, UNSPECIFIED (UNII: FZ989GH94E) SODIUM LAURYL SULFATE (UNII: 368GB5141J) MAGNESIUM STEARATE (UNII: 70097M6I30) HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO) POLYETHYLENE GLYCOL 300 (UNII: 5655G9Y8AQ) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FERRIC OXIDE RED (UNII: 1K09F3G675) FERRIC OXIDE YELLOW (UNII: EX438O2MRT)

Product CharacteristicsColor BROWN Score no scoreShape ROUND (biconvex) Size 11mmFlavor Imprint Code IRESSA;250Contains

AstraZeneca Pharmaceuticals LP

Packaging# Item Code Package Description Marketing Start

DateMarketing End

Date1 NDC:0310-0482-

3030 in 1 BOTTLE; Type 0: Not a CombinationProduct 07/13/2015

2 NDC:0310-0482-93

30 in 1 BOTTLE; Type 0: Not a CombinationProduct 07/25/2016 08/31/2019

Marketing InformationMarketingCategory

Application Number or MonographCitation

Marketing StartDate

Marketing EndDate

NDA NDA206995 07/13/2015

Labeler - AstraZeneca Pharmaceuticals LP (054743190)

Registrant - AstraZeneca PLC (230790719)

Revised: 5/2021